LB38
Breast cancer phenotype when the guardian of the genome fails
Diana Eccles1, Adrian Bateman2, Gareth Evans3, Helen Hanson4, Sue Gerty1, Nazneen Rahman4, Will Tapper1
1University of Southampton, UK, 2Southampton University Hospitals Trust, UK, 3St Mary's Hospital, Manchester, UK, 4The Institute of Cancer Research, London, UK
Aim
To establish whether the Li Fraumeni Syndrome predisposes to a consistent
breast cancer phenotype
Background
Breast cancers arising due to a genetic predisposition may tend to evolve down
a predetermined molecular pathway. BRCA1 breast cancers typically fall
into the basal subtype of triple negative tumours (ER, PR and HER2 negative).
BRCA2 associated tumours are more often in the luminal category and ER
positive but not so distinct. HER2 is amplification is rarely seen in BRCA gene
carriers. Inherited mutations in the TP53 gene lead to the Li Fraumeni
Syndrome (LFS), a rare and devastating cancer predisposition syndrome. In
classic LFS the combination of childhood soft tissue sarcoma and young onset
breast cancer (median age at diagnosis 33 years) may lead rapidly to the
diagnosis. Apparently isolated early onset breast cancer cases in two recent
studies from the USA and France found mutations in 7% of breast cancer patients
diagnosed before 30 years of age [1,2].
Method
Pathology phenotyping in 7 breast cancers in 5 patients with inherited
pathogenic TP53 mutations causing the LFS and 1 patient with 2 cancers and a
p53 variant of uncertain pathogenicity (VUS). Prospective TP53 mutation
analysis in 216 breast cancer cases aged ≤ 30 years and review of
pathology phenotype in mutation carriers compared with young onset POSH cohort.
Results
The 7 LFS associated invasive breast cancers were all high grade, and
associated with high grade comedo DCIS. The metachronous bilateral cancers in
the patient with a TP53 VUS were grade 2, ER+, PR+ and HER2 negative. The most
striking observation in those with pathogenic mutations was that 6/7 (86%)
invasive tumours showed HER2 overexpression (IHC 3+ or FISH amplified). 232
breast cancer patients from the POSH study aged 40 or younger at diagnosis [3]
were tested for HER2 amplification using CISH, 36/187 (19%) tumours
showed amplification. We tested 216 POSH study cases with breast cancer diagnosed
under 30 years and identified 4 germ line TP53 mutations (2%); all four had
high grade HER2+ (100%) breast cancers with associated high grade DCIS. We
propose that TP53 loss of function may be a very early event that predisposes
to developing HER2 positive breast cancers.
References
[1] Gonzalez, K.D. et al. Journal of Clinical Oncology (2009)
[2] Bougeard G, et al. J Med Genet. 2008 Aug;45(8):535-8
[3] Eccles, D., et al. BMC.Cancer 7.1 (2007): 160
Acknowledgements
CRUK and BCC funding
